title: Upregulation of D2-class signaling in dopamine-denervated striatum is in part mediated by D3 receptors acting on Ca V 2.1 channels via PIP2 depletion.
abstract: The loss of dopaminergic neurons in the substantia nigra compacta followed by striatal dopamine depletion is a hallmark of Parkinson's disease. After dopamine depletion, dopaminergic D(2) receptor (D(2)R)-class supersensitivity develops in striatal neurons. The supersensitivity results in an enhanced modulation of Ca(2+) currents by D(2)R-class receptors. However, the relative contribution of D(2)R, D(3)R, and D(4)R types to the supersensitivity, as well as the mechanisms involved, have not been elucidated. In this study, whole cell voltage-clamp recordings were performed to study Ca(2+) current modulation in acutely dissociated striatal neurons obtained from rodents with unilateral 6-hydroxydopamine lesions in the substantia nigra compacta. Selective antagonists for D(2)R, D(3)R, and D(4)R types were used to identify whether the modulation by one of these receptors experiences a selective change after dopaminergic denervation. It was found that D(3)R-mediated modulation was particularly enhanced. Increased modulation targeted Ca(V)2.1 (P/Q) Ca(2+) channels via the depletion of phosphatidylinositol 4,5-bisphosphate, an intracellular signaling cascade hard to detect in control neurons and hypothesized as being amplified by dopamine depletion. An imbalance in the striatal expression of D(3)R and its splice variant, D(3)nf, accompanied enhanced D(3)R activity. Because Ca(V)2.1 Ca(2+) channels mediate synaptic GABA release from the terminals of striatal neurons, reinforcement of their inhibition by D(3)R may explain in part the profound decrease in synaptic strength in the connections among striatal projection neurons observed in the dopamine-depleted striatum.
authors.affiliation: Instituto de Fisiología Celular-Neurociencias, Universidad Nacional Autónoma de México, Mexico City, Mexico.
authors.forename: G Aleph
authors.initials: GA
authors.lastname: Prieto
authors.forename: Azucena
authors.initials: A
authors.lastname: Perez-Burgos
authors.forename: Marcela
authors.initials: M
authors.lastname: Palomero-Rivero
authors.forename: Elvira
authors.initials: E
authors.lastname: Galarraga
authors.forename: Rene
authors.initials: R
authors.lastname: Drucker-Colin
authors.forename: Jose
authors.initials: J
authors.lastname: Bargas
mesh_terms: D000818:Animals; D020864:Calcium Channels, N-Type / Q000502:physiology*; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D054801:Phosphoinositide Phospholipase C / Q000172:deficiency*; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis*; D050637:Receptors, Dopamine D3 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013562:Sympathectomy / Q000379:methods; D015854:Up-Regulation / Q000502:physiology
chemical_list: D020864:Calcium Channels, N-Type; D004298:Dopamine; D054801:Phosphoinositide Phospholipase C; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3